Novel Methods for Selective Fluorination of Organic Compounds: Design and Synthesis of Fluorinated Antimetabolites

Abstract

Since 1970 we developed three novel methods of fluoro-organic synthesis in our laboratory, namely: photofluorination (R-H -> R-F); fluorodehydrozylation (R-OH -> R-F); fluorodesulfurization (R-SH -> R-F). The general idea suggesting the development of the first two of these reactions was to find one-step methods for transforming readily available and relatively complex organic compounds into the corresponding fluorine derivatives. The third method emerged as a chance discovery in an attempt to photofluorinate penicillamine, an amino acid with an SH group. The primary motivation of our search was to develop straightforward and routine syntheses of fluorine-containing antimetabolites including enzyme inhibitors. Therefore, it was very attractive to find methods of fluorination capable of transforming a metabolite into an antimetabolite in one single step. The general concept that C-ftuorinated metabolites can represent antimetabolites was already established. However, F analogs of metabolites in general were considered probes for understanding the behavior of the desfluoro metabolites rather than compounds of practical use, e.g.

Fluorinated Substrate Analogs: Routes of Metabolism and Selective Toxicity

“…In this area Kollonitsch et al at Merck (10,36,37,78) and a group at Merrell Research in Strasbourg (e.g., see Refs. 11 and 12) have systematically pioneered in the preparation, characterization, and utilization of mechanism-based inactivators of various pyridoxal-P-dependent enzymes.…”

(6S)-6-fluoroshikimic acid, an antibacterial agent acting on the aromatic biosynthetic pathway

“…For a variety of reasons (chemical stability, the requirement that compounds be amenable to total synthesis, and knowledge that shikimate is transported into bacteria) shikimic acid analogs were chosen for evaluating this approach. One strategy used in the design of potential enzyme inhibitors in medicinal chemistry is the incorporation of fluorine at regio-and stereo-specific sites (1,18). Although the precise mechanism of the transformation of EPSP to chorismate is still a matter of debate (12,15,16,20), it is well established that the C-6 pro-R hydrogen is the one that is lost in the process (12,16).…”

The use of fluoromethanes in organic synthesis

“…In many respects selectively fluorinated analogs of natural substrates are ideal probes of biological systems. The term "isogeometric transformation" has been used to describe the incorporation of fluorine in place of hydrogen to modify a molecule with "minimal distortion of geometry and concur-rent maximal effect on electron distribution" (8). This is a very important concept, in the creation of slightly altered analogs of natural substrates.…”

“…Seventy percent hydrogen fluoride in pyridine solution (11) has many advantages over gaseous or aqueous HF, including easier handling and increased selectivity. TV-Fluoropyridone (12) and AFfluorosulfonamides (13), stable solid reagents, have recently been developed as alternatives to gaseous perchloryl fluoride (FClOj) (14) and trifluoromethyl hypofluorite (CF3OF) (8) as reagents for electrophilic fluorinations.…”